bims-engexo 2026-01-04 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2026–01–04
eight papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Methods and strategies of bioengineered cell exosomes for the treatment of osteoarthritis.
Extracellular Vesicle-Mediated Delivery of Antioxidant Enzymes: Emerging Insights and Translational Opportunities.
PH20-modified exosomes loaded curcumin inhibit desmoplastic breast cancer by breaking extracellular matrix barrier and normalizing cancer-associated fibroblasts.
RDYH58 functional exosomes targeting myofibroblasts loaded with siFKBP10 for inhibition of collagen biosynthesis and secretion of IPF.
Redefining the Limits of Nanodevices-Based Drug Delivery Systems: Extracellular Vesicles.
Microglia-specific interleukin-4 delivery by engineered extracellular vesicles restores inner blood-retinal barrier in diabetic retinopathy via GAS6-MERTK pathway.
Cyanobacterial Extracellular Vesicles as Protein Carriers: Towards Fish Vaccination.
Membrane Vesicles as Drug Delivery Systems: MISEV, In Vivo Fluorescence Imaging and Tracking, Specific Tissue Targeting, and Therapeutic Application in Diseases.

Joint Bone Spine. 2025 Dec 26. pii: S1297-319X(25)00192-7. [Epub ahead of print] 106030

Methods and strategies of bioengineered cell exosomes for the treatment of osteoarthritis.

Chengjun Zhang, Jinming Liu, Shijie Chen, Dacheng Zhao, Changshun Chen, Bin Geng, Yayi Xia.

  Exosomes, as nanoscale extracellular vesicles, have emerged as vital mediators of intercellular communication through the delivery of functional cargos such as proteins, lipids, DNA, and regulatory RNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and small interfering RNAs (siRNAs). Their natural biocompatibility, targeting ability, and ability to cross biological barriers make them promising therapeutic tools for osteoarthritis (OA), a degenerative joint disease characterized by cartilage degradation and chronic inflammation. In recent years, the bioengineering of exosomes has opened new avenues for enhancing their therapeutic potential in cartilage regeneration and OA treatment. This review comprehensively summarizes recent progress in exosome engineering, including the selection of parental cells, the design and targeting of exosomes, and advanced bioengineering techniques such as RNA, protein, and drug loading, as well as surface modification. We further discuss scalable approaches for exosome purification and mass production, and the incorporation of exosomes into biomaterial scaffolds or hydrogels to enable controlled release and localized delivery. In addition, we explore therapeutic strategies involving gene therapy, chemotherapy, immunotherapy, and protein therapy, highlighting the versatility of engineered exosomes in modulating inflammation, promoting chondrocyte survival, and restoring cartilage homeostasis. Emerging technologies such as synthetic exosome mimics and vexosomes are also discussed, offering insight into future directions for enhanced delivery efficiency and clinical translation. By integrating molecular biology, materials science, and therapeutic design, engineered exosomes represent a powerful platform for precision treatment of OA. This review aims to provide a theoretical foundation and practical reference for future research and clinical application in exosome-based osteoarthritis therapy.

Keywords:  engineering exosomes; osteoarthritis; therapeutic strategies

DOI:  https://doi.org/10.1016/j.jbspin.2025.106030
Antioxidants (Basel). 2025 Dec 14. pii: 1504. [Epub ahead of print]14(12):

Extracellular Vesicle-Mediated Delivery of Antioxidant Enzymes: Emerging Insights and Translational Opportunities.

Junyu Wang, Yakun Li, Robin P F Dullaart, Peter Olinga, Han Moshage.

  Oxidative stress is a key contributor to the onset and progression of diverse pathological conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD), neurodegeneration, cardiovascular disorders, and cancer. Conventional antioxidant therapies, such as small-molecule scavengers or systemic enzyme administration, are limited by poor stability, inefficient delivery, and off-target effects. Extracellular vesicles (EVs), particularly exosomes, are increasingly recognized as natural carriers of antioxidant enzymes (AOEs), including catalase, superoxide dismutases, glutathione peroxidases, peroxiredoxins, and thioredoxin. These vesicles not only protect enzymes from degradation but also enable targeted delivery to recipient cells, where they can actively modulate redox homeostasis. In this review, we summarize current evidence for AOEs as bona fide EV cargo, outline mechanisms that govern their selective packaging and transfer, and highlight their roles in intercellular communication under physiological and pathological conditions. We also discuss emerging therapeutic applications of both natural and engineered EVs for redox modulation, along with the challenges of quantifying enzymatic activity, ensuring reproducibility, and scaling clinical translation. By integrating insights from cell biology, redox signaling, and translational research, we propose that EV-mediated AOE delivery represents a promising next-generation strategy for combating oxidative stress-related diseases.

Keywords:  antioxidant enzymes (AOEs); extracellular vesicles (EVs); intercellular communication; oxidative stress; redox signaling; therapeutic delivery

DOI:  https://doi.org/10.3390/antiox14121504
Mater Today Bio. 2025 Dec;35 102635

PH20-modified exosomes loaded curcumin inhibit desmoplastic breast cancer by breaking extracellular matrix barrier and normalizing cancer-associated fibroblasts.

Xiaoxia Xue, Xiaoyu Li, Meng Tian, Liuchunyang Yu, JinXiu Qian, Xiuyun Bai, Jue Yang, Rongjun Deng, Qiqiong Liu, Ying Xing, Yuxing Yao, Cheng Lu, Aiping Lyu, Yuanyan Liu.

  Triple-negative breast cancer (TNBC), a typical desmoplastic tumor, is characterized by dense fibrotic stroma enriched with cancer-associated fibroblasts (CAFs) and excessive extracellular matrix (ECM) deposition. Activated CAFs secrete abundant cytokine to promote tumor progression, while continuously recruit ECM proteins to form stiff pathological barriers that impede drug penetration and immune cell infiltration. In this work, we designed engineered exosomes co-modified with hyaluronidase PH20 (Exos-PH20) and curcumin (Cur) to specifically deliver Cur, aiming to breakthrough desmoplastic tumor microenvironment (TME) for deep tumor penetration, CAFs normalization rather than elimination, and amplification of anticancer efficacy. Results showed that Exos-PH20@Cur leverage the tumor-targeting capability of exosomes and PH20-mediated hyaluronan degradation to achieve deep intratumoral penetration. Meanwhile, the normalization of CAFs by suppressing PRMT5-strengthened Smad3-mediated fibrotic gene transcription, can alleviate TNBC fibrosis and even can disrupt TGF-β and IL-6 mediated crosstalk of CAFs with cancer cells to combat tumor invasion. As a result, the enhanced accumulation of Exos-PH20@Cur in tumor core, along with increased CD8+ T cells infiltration, contributed to effective cytotoxic inhibition on cancer cells. This green synthesized biocompatible nanoplatform offers a promising dual therapeutic strategy for remodeling desmoplastic TME and inhibiting tumor progression with effective drug delivery for improved TNBC therapeutic outcomes.

Keywords:  CAFs; Curcumin; Desmoplastic tumor microenvironment; Engineered exosomes; TNBC

DOI:  https://doi.org/10.1016/j.mtbio.2025.102635
Acta Pharm Sin B. 2025 Dec;15(12): 6681-6697

RDYH58 functional exosomes targeting myofibroblasts loaded with siFKBP10 for inhibition of collagen biosynthesis and secretion of IPF.

Ranran Yuan, Zhen Mu, Houqian Zhang, Yu Tian, Quanlin Xin, Qingchao Tu, Yan Zhang, Yanqiu Li, Zhiwen Zhang, Yongchao Chu, Aiping Wang, Jingwei Tian, Hongbo Wang, Chong Qiu, Yanan Shi.

  Idiopathic pulmonary fibrosis (IPF) is a complex interstitial lung disease in which myofibroblasts are the primary effector cells. FK506-binding protein (FKBP10), a procollagen chaperone, is upregulated in IPF and primarily localizes to myofibroblasts. Exosomes have garnered significant attention as novel drug delivery vehicles, particularly when engineered. However, myofibroblasts remain underexplored in terms of engineered exosome-based therapies and associated drug targets. In this study, RDYH58, a peptide that targets myofibroblasts, was conjugated to the exosomal membrane protein Lamp2b to produce RDYH58-linked exosomes (RDYH58-exo). In vitro and in vivo experiments demonstrated that compared to unmodified exosomes (unm-exo), RDYH58-exo preferentially localized to myofibroblasts. A small interfering RNA targeting FKBP10 (siFKBP10) was loaded into exosomes using ultrasonic microfluidics method, and the antifibrotic effects of RDYH58-exo carrying siFKBP10 (RDYH58-siFKBP10) were assessed both in vitro and in vivo. The results demonstrated that RDYH58-siFKBP10 effectively silenced FKBP10 gene expression, significantly inhibiting fibroblast activation and extracellular matrix deposition, with superior antifibrotic efficacy compared to unmodified exosome vectors (unm-siFKBP10). RNA-seq analysis confirmed the pivotal regulatory role of FKBP10, providing critical evidence for the development of targeted therapeutic strategies. The RDYH58-siFKBP10 delivery system developed in this study demonstrates remarkable clinical translation potential.

Keywords:  Drug delivery; Exosomes; FK506-Binding protein; Idiopathic pulmonary fibrosis; Myofibroblasts; RDYH58; Small interfering RNA; Ultrasonic microfluidics method

DOI:  https://doi.org/10.1016/j.apsb.2025.08.017
Pharmaceutics. 2025 Dec 16. pii: 1617. [Epub ahead of print]17(12):

Redefining the Limits of Nanodevices-Based Drug Delivery Systems: Extracellular Vesicles.

Marina Lucia Díaz, Victoria Simón, Luciano Alejandro Benedini, Paula Verónica Messina.

  Extracellular vesicles (EVs) are naturally occurring cell-derived vesicles that contain the same nucleic acids, proteins, and lipids as their source cells. These nano-sized systems, which are derived from a wide range of cell types within an organism and are present in all body fluids. EVs play a crucial role both in health and disease, particularly in cancer and neurodegenerative disorders. Due to their particular structure, they can function as natural carriers for therapeutic agents and drugs, akin to synthetic liposomes. EVs exhibit numerous advantages over conventional synthetic nanocarriers and other lipid-based delivery systems, including their favorable biocompatibility, natural blood-brain barrier penetration, and capacity for gene delivery. However, EVs' complex characterization and standardization, as well as being more expensive than other vesicular systems, are major drawbacks that need to be addressed before drug loading. The present review introduces the classification of EVs and their physiological roles, currently popular methods for isolating and purifying EVs, the main therapeutic approaches of EV-mediated drug delivery, and the functionalization of EVs as carriers. Consequently, it establishes novel pathways for advancing EV-based therapeutic methodologies across diverse medical disciplines. The study concludes with a discussion of the new challenges and future perspectives related to the clinical application of EVs.

Keywords:  RNA delivery; drug targeted delivery; engineered vesicles; exosomes; extracellular vesicles; nanocarriers

DOI:  https://doi.org/10.3390/pharmaceutics17121617
J Nanobiotechnology. 2025 Dec 29.

Microglia-specific interleukin-4 delivery by engineered extracellular vesicles restores inner blood-retinal barrier in diabetic retinopathy via GAS6-MERTK pathway.

Yuanyuan Fan, Pengfei Ge, Xingxing Wang, Jingyi Xu, Jingfan Wang, Hongying Li, Qinyuan Gu, Haiyue Xie, Yifan Lin, Yangyang Lu, Chengkun Wang, Ping Xie, Zizhong Hu.

  Maintaining a balanced polarization of microglia is one of the most potential therapeutic approaches for diabetic retinopathy (DR). However, reliable, sustained, effective, and controllable microglial regulation still faces formidable challenges. Here, inspired by the bioavailability and modifiability of extracellular vesicles (EV), we developed an interleukin 4 (IL4)-encapsulated and M1 microglia-targeting EV platform (IL4@CHHSSSARC-EV) for rescuing inner blood-retina barrier (iBRB) deterioration in DR. Delivery of IL4 via IL4@CHHSSSARC-EV enhanced not only the stability of IL4, but also the efficacy of anti-inflammatory phenotype (M2) shift in vitro and in vivo due to their selectivity to pro-inflammatory (M1) microglia. Treatment with IL4@CHHSSSARC-EV significantly ameliorated pathological angiogenesis and iBRB breakdown caused by hypoxia and ischemia in oxygen-induced retinopathy models, and potently minimized leakage, bleeding, lesions, pericyte loss and leukocyte adherence of vascular network in streptozotocin-induced diabetic mice with a high safety profile. Mechanistically, IL4@CHHSSSARC-EV facilitated microglial phagocytic capacity through GAS6-MERTK signaling, thereby engulfing aberrant vessels and disrupting the reciprocal crosstalk between microglia and pathological vasculature. Our study demonstrated that engineering EV as an enduring, efficient and safe implement for manipulating microglia provided a potential strategy for a rebalanced immune profile in DR.

Keywords:  Blood-retina barrier; Diabetic retinopathy; Engineered extracellular vesicles; Microglia; Targeted delivery

DOI:  https://doi.org/10.1186/s12951-025-03976-w
Microb Biotechnol. 2026 Jan;19(1): e70294

Cyanobacterial Extracellular Vesicles as Protein Carriers: Towards Fish Vaccination.

Jorge Matinha-Cardoso, Gabriela Gonçalves, Filipe Coutinho, Steeve Lima, Lourenço Bonneville, Mónica Serrano, Paula Tamagnini, Aires Oliva-Teles, Ana Couto, Cláudia R Serra, Paulo Oliveira.

Fish aquaculture faces significant economic losses from disease outbreaks. Vaccination is the most effective prevention strategy, and bacterial extracellular vesicles (EVs) show promise as vaccine platforms due to their strong immuno-stimulating properties. However, the application of EVs derived from pathogenic bacteria is limited by toxicity risks and production challenges. Alternatively, genetic engineering of non-pathogenic microorganisms is being explored to produce tailored EVs to deliver antigens and serve as carriers of therapeutic proteins. Recently, we have engineered the model cyanobacterium Synechocystis sp. PCC 6803 for the expression of the reporter green fluorescent protein (sfGFP) and its targeting to EVs. Here, taking advantage of the Synechocystis sfGFP-loaded EVs, the stability of vesicles and their cargo was evaluated in the long term when stored under different temperature conditions and after freeze-drying. The possibility of using Synechocystis EVs as a tool for eliciting specific/adaptive immune responses was assessed in European seabass, a high commercial value fish, by following the amount of total and sfGFP-specific immunoglobulins produced after immunisation through injection. Synechocystis EVs were shown to be resilient nanostructures that can induce specific immune responses in fish with additional adjuvant features. This represents a biotechnological breakthrough towards a novel antigen-carrier platform for sustainable fish-pathogen control.

DOI: https://doi.org/10.1111/1751-7915.70294
Pharmaceutics. 2025 Nov 30. pii: 1550. [Epub ahead of print]17(12):

Membrane Vesicles as Drug Delivery Systems: MISEV, In Vivo Fluorescence Imaging and Tracking, Specific Tissue Targeting, and Therapeutic Application in Diseases.

Ying Qin, Hongda Zhuang, Xiaoyong Ren, Mengyi Lan, Shuoshuo Fan, Zhitao Qiu, Junfang Zhao, Yong Chen.

  In the last decade, notable developments have occurred regarding the application of membrane vesicles-encompassing extracellular vesicles (EVs, including exosomes, microvesicles, apoptotic bodies, and others), self-organized cellular-membrane-derived vesicles, and isolated cell-bound membrane vesicles, among others-as bioinspired drug delivery systems (DDSs). A collection of 10 papers on such advances was published in the Special Issue of Pharmaceutics entitled "Advances of membrane vesicles in drug delivery systems, 2nd Edition". These papers investigate the Minimum Information for Studies of Extracellular Vesicles (MISEV), in vivo fluorescence imaging and tracking, in vivo specific tissue targeting, and the therapeutic application of membrane vesicles as DDSs in cancers, osteoarthritis, ocular disorders, intestinal disease, and kidney diseases. The present article briefly summarizes these related topics and provides novel insights into the research on membrane vesicles as DDSs.

Keywords:  drug delivery systems (DDSs); fluorescence imaging and tracking; membrane vesicles; specific tissue targeting; therapeutic applications

DOI:  https://doi.org/10.3390/pharmaceutics17121550